7alpha-methyl-13beta-alkyl-17alpha-hydrocarbyl-17beta-oxy-delta4,9,11-gonatrene-3-ones

ABSTRACT

A novel process for the preparation of 7 Alpha -methyl-13 Beta R-17 Alpha -X-17 Beta -OY- Delta 4,9,11-gonatriene-3-ones of the formula   WHEREIN R is lower alkyl of one to four carbon atoms, X is saturated or unsaturated, substituted or unsubstituted, straight or branched aliphatic hydrocarbon of one to four carbon atoms and Y is selected from the group consisting of hydrogen and acyl of an organic carboxylic acid of one to 18 carbon atoms and novel intermediates formed therein.

United States Patent Bucourt et al.

[4 1 March 6, 1973 7a-METHYL-13B-ALKYL-l7a- HYDROCARBYL-l7B-OXY-A4,9,ll- GONATRENE-3-ONES Inventors: Robert Bucourt; Lucien Nedelec,

both of Clichy-sous-Bois; Jean- Claude Gasc, Bondy, all of France Assignee: Roussel Uclaf, Paris, France Filed: July 27, 1970 Appl. No.: 58,666

Foreign Application Priority Data July 28, 1969 France ..6925700 US. Cl ..260/397.45, 260/239.55 C, 260/999 Int. Cl ..C07c 167/14 Field of Search ../Machine Searched Steroids References Cited UNITED STATES PATENTS 11/1966 Joly et al. ..l67/65 7/1969 Vignau et al. ..260/239.55

Edwards ..260/239.55 Berlin et al ..260/397.45

Primary Examiner-Henry A. French Attorney-Hammond & Littell [57] ABSTRACT A novel process for the preparation of 7a-methyl- 1 3B- R-l7a-X-l7B-OY-A- -gonatriene-3-ones of the formula 0 O; V H I 4 Claims, No Drawings 7a-METI-IYL-1 3B-ALKYL- l 7a-HYDROCARBYL- l7B-OXY-A4,9,l1-GONATRENE-3-ONES OBJECTS OF THE INVENTION It is an object of the invention to provide a novel process for the preparation of the A- --gonatriene of Formula I.

It is another object of the invention to provide novel intermediates produced in the process of the invention.

These and other objects and advantages of the invention will become obvious from the following described description.

THE INVENTION The novel process of the invention for the preparation of 7a-methyl-A -gonatrienes of the formula I f OY m \\\X /w CH3 wherein R is loweralkyl of one to four carbon atoms, X is saturated or unsaturated, substituted or unsubstituted, straight or branched aliphatic hydrocarbon of one to four carbon atoms and Y is selected from the group consisting of hydrogen and acyl of an organic carboxylic acid of one to 18 carbon atoms comprises reacting a 7a-methyl-A -gonene of the formula Haj W TCH wherein R has the above definition and Ac is acyl of an organic carboxylic acid with a dehydrating agent to form a mixture of dehydrated products, reacting the said mixture in acid media with a ketalization agent capable of forming a cyclic ketal to form a compound of the formula V R 0A0 A I IT 0 Rl j l O W 3 In wherein R is an alkylene, saponifying the latter with a basic agent to form a compound of the formula subjecting the latter to the action of an oxidizing agent to form a compound of the formula reacting the latter with an organic metallic derivative to obtain a compound of the formula where X has the above definition, esterifying, if desired, the said compound to form the corresponding l7/3-OY compound hydrolyzing the latter compound in an acidic media to form a compound of the formula VII oxidizing the latter with oxygen in the presence of a tertiaryamine to form a compound of the fonnula R OY llOO

subjecting the latter to the action of a reducing agent to form a compound of the formula VIII 3 propene-l-yl, chloroethynyl and 2-methyl-propene-2- yl.

Examples of suitable organic acids of one to 18 carbon atoms may be derived from an aliphatic, aromatic, cyclo-aliphatic or heterocyclic carboxylic acid. Examples of suitable acids are alkanoic acids, such as formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethyl acetic acid, caproic acid, 3-trimethyl propionic acid, heptanoic acid, caprylic acid, pelargonic acid, capric acid, undecyclic acid, lauric acid, myristic acid, palmitic acid and stearic acid; alkenoic acids, such as undecylenic acid and oleic acid; cycloalkyl carboxylic acids, such as cyclopentyl carboxylic acid, cyclopropyl carboxylic acid, cyclobutyl carboxylic acid and cyclohexyl carboxylic acid; cycloalkyl alkanoic acids, such as cyclopentyl acetic acid, cyclohexyl acetic acid, cyclopentyl propionic acid and cyclohexyl propionic acid; arylalkanoic acids, such as phenyl acetic acid and phenyl propionic acid; aryl carboxylic acids, such as benzoic acid and 2, 4-dinitrobenzoic acid; phenoxy alkanoic acids such as phenoxy acetic acid, p-chlorphenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4-ter-butylphenoxy acetic acid, 3-phenoxy propionic acid and 4-phenoxy butyric acid; heterocyclic carboxylic acids, such as furane-Z-carboxylic acid, 5-terbutylfurane-2- carboxylic acid, 5-bromo-furane-2-carboxylic acid and nicotinic acids; 3-ketoalkanoic acids, such as acetylacetic acid, propionylacetic acid and butyrylacetic acid; amino acids, such as diethylaminoacetic acid and aspartic acid.

The compounds of Formula I possess interesting endocrinic properties which may be used as anabolic agents for the treatment of thinness or osteoporose or an androgenic agent for the treatment of adiposo genitious syndromes, or as a progestative agent for the treatment of sterility or repeated abortions or as hypophysial inhibitory agents for arresting ovaries or treatment of sexual hypersecretions.

Examples of specific compounds of formula I are 70:, l 7a-dimethyl-l 3ds-ethyl-A-- -gonatriene-l 73-01-3- one, 7a, l7a-dimethyl-l 33-ethyll 73-acetoxy-A gonatriene-3-one, 7a, l7a-dimethyll 33ethyll 73- propionyloxy-A -gonatriene-3-one, 7a, 170:- dimethyl-l 33-ethyl-l 73-benzoxyloxy-A" gonatriene-3-one, 7a, l7a-dimethyll 33-propyl-A- gonatriene-l 7301 -3-one, 7a, l7a-dimethyll 33- propyl-l 73-benzoyloxy-A -gonatriene-B-one, 7amethyl-l 33-ethyll 7a-ethynyl-A -gonatriene-l7 30 l -3-one, 7a-methyl- 1 33-ethyl- 1 7a-( 2-methylpropene-Z-yl)-A -"-gonotriene-l 73-01 -3-one, 7amethyl-l33-ethyl-l "la-allyl-A -gonatriene-l 73-01-3 -one, 7a-methyll 33-ethyll 7cz-chloroethynyl-A""- gonatrienel 73-ob-3-one, 7a -methyl- 1 33-ethyl- 1 7avinyl-A -gonatriene-173-ol-3-one, 7a-methyll 33- propyl-l 7a-ethynyl-A- -gonatriene- 1 73-0 1 -one, 7amethyl- 1 33-propyl-l 7avinyl-A- -gonatriene- 1 73-0 1 3-one and 70117a-dimethyl-l33-propyl-l73-acetoxy- A -gonatriene-3-one.

One of the characteristics of the invention are the novel intermediates of the formula wherein R, R, X and Y have the above definitions. The said gonadienes have an industrial interest as being intermediates from which the gonatrienes of formula I are easily accessible and the said gonatrienes have a 5 well-known considerable physiological activity.

Examples of novel intermediates of formula Va are 3,3-ethylenedioxy-7a, l7a-dimethyll 73-acetoxy- A -estratriene. 3,3-ethylendioxy-7a, dimethyl-,73-propionoyloxy-A "-estradiene, 3,3- ethylenedioxy-7qz, l 7a-dimethyl-l 73-benzoyloxy- A -estradiene, 3,3-ethylenedixoy-7zx, 17adimethyl-l33-ethyl-A gonadiene-l73-ol, 3,3- ethylenedioxy-7a, 1 7a-dimethyll 33ethyll 73-acetoxy-A -gonadiene, 3, 3-ethylenedioxy-7a, 17adimethyll 33-ethyll 73-propionyloxy-A gonadiene, 3, 3-ethylenedioxy-7a, l7a-dimethyl-l73 benzoyloxy-A -gonadiene, 3, 3-ethylenedioxy- 7a, l7a-dimethyl-l 33-propyl-A "-gonadiene- 173-01, 3, 3-ethylenedioxy-7a, l7a-dimethyl-l33- propyll 73acetoxy-A -gonadiene, 3 ,3- ethylenedioxy-7a, l7a-dimethyl-l 33-propyl-1 73- benzoyloxy-A -gonadiene, 3, 3-ethylenedioxy- 7a-methyll 7a-ethynyl-A -estradiene- 1 73-01 3 ,3-ethylenedioxy-7a-methyl- 1 7a-( 2-methyl-propene- 2-yl)-A "-estradiene- 1 73-01 3 3-ethylenedioxy- 7a-methyll 7a-allyl-A -estradiene-l 73-01 3 3- ethylenedioxy-7oz-methyll 7a-chloroethynyl-A estradiene-l73-ol 3, 3-ethylenedioxy-7a-methyl-l 7avinyl-A'"- -gonadiene-l 73-01 3 3-ethylenedioxy- 7a-methyll 33-ethyll 7a-ethynyl-A "-gonadiene- 173-0 1 3, 3-ethylenedioxy-73-methyll 33-ethyl-l 7a- (2-methyl-propene-2-yl )-A -gonadiene-l 73-01 3 3-ethylenedioxy-7a-methyll 33-ethyll 7aallyl- M -gonadiene- 173-dl, 3T3-ethyleiTediaF7E- methyl- 1 33-ethyll 7a-vinyl-A "-gonadiene-l 73- 01 3 ,3-ethylenedioxy-7a-methyll 33-ethyl-l 7achloroethynyl-A -gonadiene-173-01,3 ,3- ethylenedioxy-7a-methyl-l 33-propyl-l 7a-ethynyl- A -gonadiene- I 73-01 3 ,3-ethylenedioxy-7amethyl l33-propyll 7avinyl-A "-gonadienel 73- 01 and 3,3-ethylenedioxy-7a, 17a -dimethyl-A estradiene- 1 73-0 1 For the process of the invention, the dehydrating agent is preferably N-bromo-acetamide in the presence of sulfurous acid anhydride although one may use phosphorus oxychloride or thionyl chloride in the presence of pyridine and the resulting dehydration product is a mixture and of diverse dienic compounds characterized by infrared and ultraviolet spectra whose double bonds may be conjugated [5(l0),9(1l) or 4,9]

or non-conjugated [4,9(l l) or 4,! l]. The action of the.

ketalization agent with this mixture leads principally to the 3 ketal of 7a-methyl-l33-R-l73-acyloxy-A gonadiene-3-one. The ketalization agent is preferably ethylene glycol or 2-methyl-2-ethyl-dioxolane. Ethylene glycol in the presence of pyridine hydrochloride is most preferred.

The basic agent to saponify the 17a acyloxy function of the compound of formula III is preferably an alkali metal hydroxide such as potassium hydroxide and the saponification is effected in an alcohol such as methanol. The oxidation of the l73-OH group of the compound of formula IV is effected by the Oppenauer reaction using a lower aliphatic ketone such as acetone, methyl ethyl ketone, methyl iso butyl ketone or a cyclic ketone such as cyclo hexanone in the presence of an aluminum secondary alcoholate such as aluminum isopropylate.

The introduction of the l7asubstituent may be realized with an organometallic compound of organo lithium type XLi or of XMgl-lal type where Hal is a halogen such as chlorine or bromine. The esterification of the 173-011 group of a compound of formula V may be effected with the usual esterification agents such as the free acids, acid anhydride or acid chloride. The acid hydrolysis of the 3-keta1 group may be an organic acid such as citric acid or acetic acid. The hydrolysis is advantageously effected in the presence of several solvents such as alcohols, i.e. ethanol or methanol or a hydrocarbon such as benzene or toluene.

The peroxide formation is effected with oxygen in the presence of a tertiary amine, preferably triethylamine or pyridine and in an organic solvent such as methanol, ethanol or a N, N-dialkylamide such as dimethyl formamide. The reduction of the hydroperoxy group is preferably effected with triethyl phosphite, trimethyl phosphite or an alkali metal iodide such as potassium iodide.

The acid used to form the A -gonadiene is preferably a strong mineral acid such as perchloric acid or sulfuric acid or an organic acid such as formic acid on p-toluene sulfonic acid or a Lewis acid such as boron trifluoride. The nucleophilic agent is preferably an organic acid nitrile such as acetonitrile, malonic dinitrile, dichloroacetonitrile, etc. or an alkali metal cyanide such as sodium cyanide or potassium cyanide. The aprotic solvent may be methylene chloride, chloroform, cyclohexane, benzene, ethyl ether or tetrahydrofuran.

The starting 7a-methyll Bfl-R- l 7B-acyloxy-A gonene -1 1 (8-0 l-3-one of formula II can be prepared by the process of commonly assigned U. S. patent application Ser. No. (58,668) filed on even date herewith which process comprises reacting a 13l3-R-N-gonene- 11B, 17,8-diol-3-one (prepared by process of French patent No. 1,574,693) with an acylating agent or a mixture of acylating agents to obtain the corresponding 3,113, 17a-triaycloxy-13B-R -A -gonadiene, reacting the latter with an appropriate brominating agent to selectively brominate in the six-position, dehydrobrominating the latter with a lithium halide in the presence of a basic agent to obtain 11B, 17a-diacyloxy-l3B-R-A"-gonadiene-3-one, reacting the latter with an organo metallic agent containing a methyl group, preferably in the presence of a catalyst such as cuprous chloride then saponifying with a base the incompletely cleaved esters to obtain 7a-methyl-13B-R- A -gonene-l 1B, 17B-diol-3-one which is acylated in the 17 position by known methods.

In the following examples there are described several preferred embodiments to illustrate the invention. However, it should be understood that the invention is not intended to be limited to the specific embodiments.

STEP A: 3,3-ethylenedioxy-7a-methyl-1 3B-ethyl-17B- acetoxy-A -gonadiene 19.4 gm of 7a-methy1-13B-ethyl-17B-acetoxy- Agonened lB-ol-3-one [prepared as in copending, commonly assigned U. S. patent application Ser. No. 58,668 filed on even date herewith] were dissolved in 240 cc of pyridine under a nitrogen atmosphere and after the addition of 1 1 gm of N-bromo-acetamide, the mixture was stored at room temperature for 15 minutes. The mixture was cooled to 0C. and sulfurous dioxide was bubbled through the reaction mixture until a amide-iodide paper test was negative. The reaction mixture was added to ice-water mixture and the aqueous phase was extracted with methylene chloride. The methylene chloride extracts were washed with an aqueous hydrochloric acid solution, with water, were dried and concentrated to dryness to obtain 18.7 gm of a raw dehydrated mixture.

The said 18.7 gm of raw product were dissolved under a nitrogen atmosphere in a mixture of 945 cc of chloroform and 94.5 cc of ethylene glycol and 18.7 gm of the hydrochloric salt of pyridine were added thereto. The reaction mixture was refluxed for 18 hours and after cooling was added to a water-ice mixture. The aqueous phase was extracted with methylene chloride and the methylene chloride extracts were washed with a saturated aqueous sodium bicarbonate solution, were dried and concentrated to dryness. The residue was empasted with a 1-1 mixture of iso propyl ether and petroleum ether (b.p.=3570C) to obtain 11.69 gm of 3,3-ethy1enedioxy-7a-methyll 3B-ethyl-1 7B-acetoxy-A "-gonadiene melting at 151C.

U. V. Spectrum (ethanol):

Max. at 236-237 mu =17,900 Max. at 243 mp. e=19,400 lnflexion towards 250 mp. 'e=l3,000

By chromatography over silica gel of the empasting mother liquors and elution with a 1-1 mixture of ethyl ether and petroleum ether (Bp=35-70C.), a second crop of 3.19 gm of 3,3-ethylenedioxy-7a-methyl-13B- ethyl-17B-acetoxy-A gonadiene melting at 150C. were obtained.

As far as is known, the latter product is not described in the literature.

STEP B: 3,3-ethylenedioxy-7a-methyl-13B-ethyl-A -gonadiene- 1 -01 14.8 gm of 3,3-ethylenedioxy-7a-methyl-13B-ethyl- 17B-acetoxy-A -gonadiene were added under a nitrogen atmosphere to a mixture of 148 cc of methanol and 14.8 cc. of a 50Be' aqueous potassium hydroxide solution and the mixture was heated to reflux and held there for 30 minutes. After cooling, the mixture was poured into a water-ice mixture and stirred. The precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 12.8 gm of 3 ,3-ethylenedioxy-7a-methyl- 1 3 B-ethyl-A -gonadiene-l 73-01 melting at 148C.

U.V. Spectrum (ethanol):

Max at 237 my. 00 Max at 244 mp. e=l9,400 Max at 252 mu =l2,550

As far as is known, this compound is not described in the literature. STEP C: 3,3-ethylenedioxy-7a-methyl-l3B-ethyl-A ""gonadienel 7 -one.

gm of 3,3 ethylenedioxy-7a-methyl-13B-ethyl-A ""-gonadiene-173-01 was added under a nitrogen atmosphere to a mixture of 250 cc of toluene and 50 cc of cyclohexanone and the mixture was refluxed to eliminate by distillation 50 cc of toluene. A solution of 5 gm of aluminum isopropylate in 250 cc of toluene was added thereto while continuing distillation to keep a constant reaction volume. Then, a solution of 2.5 gm of aluminum isopropylate in 125 cc of toluene and then a solution of 50 gm of potassium and sodium tartrate in 300 cc of water were added thereto. The solvent was removed by intrainment as a vapor and ice was then added and the mixture was stirred. The aqueous phase was extracted with ethyl ether and the ether extracts were washed with water, were dried and concentrated to dryness under reduced pressure. The residue was purified by chromatography over silica gel with elution with a 3-1 mixture of ethyl ether-petroleum ether (BP=3570C.) The homogenous fractions were crystallized from isopropyl ether to obtain 7.73 gm of 3 ,3-ethylenedioxy-7a-methyl-1SB-ethyI-A gonadiene-17-one-melting at 101C.

U. V. Spectrum (ethanol):

lnflex.towards 231 mp e=l8,500 Max. at 243-244 mg. c=l9,600 lnflex. towards 251 my. =12,600

As far as is known, this compound is not described in the literature. STEP D: 3,3-ethylenedioxy-7oz, l7a-dimethy1-13B- ethyl-A "-gonadiene-173-01 7.65 gm of 3,3-ethylenedioxy-7a-methyl-l3B-ethyl- A -"-gonadiene-l7-0ne were dissolved under a nitrogen atmosphere in 1 cc of ethyl ether and while cooling the solution to 5C., 276 cc of a 0.65 M ether solution of methyl lithium were added. The mixture was stirred for 3 hours at 5C. and was then poured into a mixture of water, ice and ammonium chloride. The ether phase was decanted off and the aqueous phase was extracted with ethyl ether. The combined ether phases were washed with water, dried and concentrated to dryness. The residue was purified by chromatog'raphy over silica gel to obtain 5.62 gm of 3,3- ethylenedioxy-7a, l7a-dimethy1-13B-ethyl-A" gonadiene-17B-ol melting at 128C. U. V. Spectrum (ethanol):

Max. at 236-237 mp. e=l9,000 Max. at 244-245 mp. FZOAOO lntlex. towards 251-252 my. e=13,300

As far as is known, this compound is not described in the literature. STEP E: 70:, 17a-dimethyl-13fl-ethyl-A gonadiene-17B-ol-3-one 5.55 gm of 3,3-ethylenedioxy-7a, l7a-dimethyl-13B- ethyl-A -""-gonadiene-17/3-01 were added to 278 cc of 75 percent aqueous acetic acidand the mixture was stirred at room temperature for Srhours. The reaction mixture was poured into a water-ice mixture and the aqueous phase was extracted with methylene chloride. The methylene chloride extracts were washed with an aqueous sodium bicarbonate solution, then with water, dried and evaporated to dryness to obtain 5.07 gm of raw 7a, 17a-dimethyl-13fl-ethyl-A "-gonadiene- 17-[3-o1-3-one which was used as is for the next step.

As far as is known, this compound is not described in the literature. STEP F: l7a-dimethyl-l 1,8-hydroperoxy-13B- ethyl-A--gonadienel 7B-ol-3-one 5.07 gm of raw 7oz, l7a-dimethyl-13fl-ethyl-A -g6nadiene-17B-dl-3-one were dissolved in 126 cc of ethanol containing 1 percent of triethylamine and oxygen was bubbled through the solution for 8 hours. The reaction mixture was concentrated to dryness under reduced pressure to obtain 6 gm of raw 7a, 17adimethyl-l lB-hydroperoxy-l 3B-ethyl-A-'-gonadienel7B-ol-3-one which was used for the next step as is.

As far as is known, this compound is not described in the literature. STEP G: 7a, l7a-dimethyl-l3B-ethyl-A- --gonadiene- 1 1B,17B-diol-3-one 6 gm of the raw hydroperoxide obtained in Step F were dissolved in 53.5 cc of ethanol and after the addition of 4 cc of triethylphosphite solution thereto, the mixture was refluxed minutes. After cooling, excess phosphite was destroyed by the addition of an aqueous oxygenated water solution and the reaction mixture was poured into a water-ice mixture. The aqueous phase was extracted with ethyl ether and ether extracts were washed with water, dried and concentrated to dryness. The residue was purified by chromotography over silica gel and elution with a 7-3 mixture of chloroform and acetone and the fraction obtained was crystallized from a 8-2 mixture of isopropyl ether- Max. at 216-217 mp F4,600 Max. at 235 mp. 1=4,500 Max. at 301-302'mp $18,050

As far as is known, this compound is not described in the literature. STEP H: 70:, 17a-dimethyl-l 3B-ethyl-A""- gonatriene-l 7B-ol-3-one 1.6 gm of 7a, l7oz-dimethyl-l3B-ethyl-A gonadiene-l 1B, l7B-diol-3-one were dissolved under a nitrogen atmosphere in a mixture of 32 cc of methylene chloride (pure except for methanol)and 6.5 cc of acetonitrile and then 1.34 cc of an aqueous solution of 55 Be perchloric acid were added thereto. The mixture was stirred for 2 minutes at room temperature, and then was poured rapidly into a water-ice mixture. The aqueous phase was extracted with methylene chloride and the methylene chloride extracts were washed with an aqueous sodium bicarbonate solution, then with water, dried and concentrated to dryness. The residue was dissolved in methylene chloride and the solution was passed through an alumina column and concentrated to dryness. The resulting dried extract was crystallized from a 1-1 mixture of isopropyl ethermethanol to obtain 1.025 gm of 7a, l7a-dimethyl-13B- ethyl-A -gonatriene-l7B-ol-3-one melting at C.

and having a specific rotation [a] =l42 (c==o.75 percent in chloroform). U. V. Spectrum (ethanol):

Max. at 240-241 mp. 65,750 Max. at 269-270 ml. -3300 Max. at 282 mp. 1-4100 Max. at 344 mp. 829250 RMN Spectrum (deuterochloroform):

Peaks at 43-495 hz (hydrogens of 7-methyl); at 5360.3-hz (hydrogens of l3-ethyl); at 76.3 hz (hydrogens of l7a-methyl); at 347 hz (hydrogen at four position); and at 374-33 84.2-392 hz (hydrogens at 11 and 12).

As far as is known, this compound is not described in the literature.

Various modifications of the products and process of the invention may be made without departing from the spirit or scope thereof and it is to be understood that the invention is to be limited only as defined in the appended claims.

We claim:

1. A process for the preparation of a 7a-methyl-A "*--gonatriene of the formula wherein R is lower alkyl of one to four carbon atoms, X is saturated or unsaturated straight or branched aliphatic hydrocarbon of one to four carbon atoms optionally substituted with chlorine and Y is selected from the group consisting of hydrogen and acyl of an organic carboxylic acid of one to 18 carbon atoms, comprising reacting a 7a-methyl-A-gonene of the formula R OAc C Ha a M R g OK;

i) U "1 a wherein R is an alkylene, saponifying the latter with a basic agent to form a compound of the formula subjecting the latter to the action of an Oppenhauer oxidizing agent to form a compound of the formula reacting the latter with an organo metallic derivative selected from the group consisting of organo lithium and organo magnesium halide to obtain a compound of the formula wherein X has the above definition, esterifying, if desired the said compound to form the corresponding 17B-OY compound, hydrolyzing the latter compound in an acidic media to form a compound of the formula (L- "CH3 oxidizing the latter with oxygen in the presence of a tertiary amine to form a compound of the formula subjecting the latter to the action of a reducing agent selected from the group consisting of trimethyl phosphite, triethyl phosphite and alkali metal iodides to form a compound of the formula reacting the latter with an acid selected from the group 1 consisting of a strong mineral acid, a Lewis acid and an organic acid in an aprotic solvent in the presence of a nucleophilic agent selected from the group consisting of organic acid nitrile and alkali metal cyanide to obtain the desired 7amethyl-A-- -gonatriene.

0 consisting of perchloric acid, sulfuric acid, formic acid,

P-toluene sulfonic acid and boron trifluoride.

k w k 

1. A process for the preparation of a 7 Alpha -methyl- Delta 4, 9,11-gonatriene of the formula wherein R is lower alkyl of one To four carbon atoms, X is saturated or unsaturated straight or branched aliphatic hydrocarbon of one to four carbon atoms optionally substituted with chlorine and Y is selected from the group consisting of hydrogen and acyl of an organic carboxylic acid of one to 18 carbon atoms, comprising reacting a 7 Alpha -methyl- Delta 4-gonene of the formula wherein R has the above definition and Ac is acyl of an organic carboxylic acid with a dehydrating agent selected from the group consisting of N-bromoacetamide, thionyl chloride and phosphorus oxychloride to form a mixture of dehydrated products, reacting the said mixture in acid media with a ketalization agent capable of forming a cyclic ketal to form a compound of the formula wherein R1 is an alkylene, saponifying the latter with a basic agent to form a compound of the formula subjecting the latter to the action of an Oppenhauer oxidizing agent to form a compound of the formula reacting the latter with an organo metallic derivative selected from the group consisting of organo lithium and organo magnesium halide to obtain a compound of the formula wherein X has the above definition, esterifying, if desired the said compound to form the corresponding 17 Beta -OY compound, hydrolyzing the latter compound in an acidic media to form a compound of the formula oxidizing the latter with oxygen in the presence of a tertiary amine to form a compound of the formula subjecting the latter to the action of a reducing agent selected from the group consisting of trimethyl phosphite, triethyl phosphite and alkali metal iodides to form a compound of the formula reacting the latter with an acid selected from the group consisting of a strong mineral acid, a Lewis acid and an organic acid in an aprotic solvent in the presence of a nucleophilic agent selected from the group consisting of organic acid nitrile and alkali metal cyanide to obtain the desired 7 Alpha methyl-Delta 4,9,11-gonatriene.
 2. The process of claim 1 wherein the dehydrating agent is N-bromo-acetamide in the presence of sulfurous acid anhydride.
 3. The process of claim 1 wherein the ketalization agent is selected from the group consisting of ethylene glycol and 2-methyl-2-ethyl-dioxolane. 